基于PPAR-γ信号通路相关基因甲基化探讨益气活血中药改善胰岛素抵抗合并动脉粥样硬化的作用机理

The prognosis of cardiovascular events in type 2 diabetes mellitus (T2DM) is equal to that found in patients with coronary heart diseases (CHD) not associated with T2DM. Insulin resistance (IR) is one of the important mechanisms of atherosclerosis (AS) in patients with T2DM. The methylation of PPAR-γ signaling pathway is closely related to IR and AS. Therefore, we hypothesized that abnormal gene methylation of PPAR-γ signaling pathway may increase insulin sensitivity and inhibit AS. There is no study of traditional Chinese medicine aiming at gene methylation regulation in AS. IR and AS are closely related to the state of qi deficiency and blood stasis in traditional Chinese medicine. Previous studies showed that Chinese herbs for benefiting qi and activating blood circulation have definite improvements in insulin resistance and anti atherosclerosis, and have the intervention effect on PPAR-γ gene expression. However, it is not reported that whether the mechanism is related with gene methylation. In this study, we make the insulin resistant model of macrophagea in vitro and type 2 diabetes ApoE-/- mice with atherosclerosis. Secondly, we observe gene methylation of PPAR-γ signaling pathway in insulin resistance and atherosclerosis, and the effect of Yiqi Huoxue Chinese herbs. Our study could provide the experimental basis for the prevention and treatment of type 2 diabetes mellitus and atherosclerosis.

2型糖尿病（T2DM）是冠心病的等危症。胰岛素抵抗（IR）是T2DM患者发生动脉粥样硬化（AS）的重要机理之一，PPAR-γ信号通路相关基因异常甲基化与IR和AS均密切相关。因此，我们推测，改善PPAR-γ信号通路相关基因异常甲基化可增加胰岛素敏感性、抑制AS进展。以基因甲基化为治疗靶点的抗AS中药研究尚处于空白状态。IR并AS发生与中医“气虚血瘀”状态密切相关。前期研究表明，益气活血中药（西洋参茎叶总皂苷和芎芍胶囊）有明确的改善IR、抗AS作用，且对PPAR-γ基因表达有干预效应，但是否通过调控基因甲基化未见报道。本研究通过体外构建胰岛素抵抗状态下的巨噬细胞源泡沫细胞模型，体内构建胰岛素抵抗并动脉粥样硬化小鼠复合模型，以“PPAR-γ信号通路相关基因甲基化”为切入点，分析益气活血中药改善IR、抗AS的新分子机制和作用环节，为临床中医药防治2型糖尿病并动脉粥样硬化提供新的科学依据。

2型糖尿病（T2DM）是冠心病的等危症。胰岛素抵抗（IR）是T2DM患者发生动脉粥样硬化（AS）的重要机理之一，研究发现相关基因异常甲基化可增加胰岛素敏感性、抑制AS进展。以 基因甲基化为治疗靶点的抗AS中药研究尚处于空白状态。IR并AS发生与中医“气虚血瘀”状态 密切相关。前期研究表明，益气活血中药洋参芎芍方能补气养阴、活血化瘀，前期研究表明该方能调节糖脂代谢、抑制AS，全基因组甲基化测序发现该方具有促甲基化作用益气活血中药（西洋参茎叶总皂苷和芎芍胶囊）有明确的改善IR、抗AS作用。本研究 通过体外构建胰岛素抵抗状态下的巨噬细胞源泡沫细胞模型，体内构建胰岛素抵抗并动脉粥样硬化小鼠复合模型，发现益气活血中药洋参芎芍方可有效改善糖尿病动脉粥样硬化，其机制可能与通过调控相关基因甲基化改善糖脂代谢及炎症反映有关，本课题为临床中医药防治2型糖尿病并动脉粥样硬化提供新的科学依据。本课题已发表课题相关SCI论文一篇，拟培养两名博士研究生，一名已毕业。